US20110152333A1 - 3-cyanopyrrolidinyl-phenyl-oxazolidinones as antibacterial agents - Google Patents
3-cyanopyrrolidinyl-phenyl-oxazolidinones as antibacterial agents Download PDFInfo
- Publication number
- US20110152333A1 US20110152333A1 US13/002,097 US200913002097A US2011152333A1 US 20110152333 A1 US20110152333 A1 US 20110152333A1 US 200913002097 A US200913002097 A US 200913002097A US 2011152333 A1 US2011152333 A1 US 2011152333A1
- Authority
- US
- United States
- Prior art keywords
- compound
- phenyl
- formula
- group
- acetamide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 0 [1*]C1=C(N2CCC([N+]#[C-])C2)C([2*])=CC(N2C[C@H](CNC([3*])=O)OC2=O)=C1 Chemical compound [1*]C1=C(N2CCC([N+]#[C-])C2)C([2*])=CC(N2C[C@H](CNC([3*])=O)OC2=O)=C1 0.000 description 9
- HYLRPUOWWIHHNE-ABLWVSNPSA-N CC(=O)NC[C@H]1CN(C2=CC(F)=C(N3CCC(O)C3)C=C2)C(=O)O1 Chemical compound CC(=O)NC[C@H]1CN(C2=CC(F)=C(N3CCC(O)C3)C=C2)C(=O)O1 HYLRPUOWWIHHNE-ABLWVSNPSA-N 0.000 description 1
- TYZROVQLWOKYKF-ZDUSSCGKSA-N CC(=O)NC[C@H]1CN(C2=CC(F)=C(N3CCOCC3)C=C2)C(=O)O1 Chemical compound CC(=O)NC[C@H]1CN(C2=CC(F)=C(N3CCOCC3)C=C2)C(=O)O1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 1
- LSNZLLQBWYCEEF-YUZLPWPTSA-N CC(NC[C@@H](CN1c(cc2F)cc(F)c2N(CC2)CC2C#N)OC1=O)=O Chemical compound CC(NC[C@@H](CN1c(cc2F)cc(F)c2N(CC2)CC2C#N)OC1=O)=O LSNZLLQBWYCEEF-YUZLPWPTSA-N 0.000 description 1
- WSRDPIRQDIOHNS-UHFFFAOYSA-N N#CC(CC1)CN1c(ccc(NC(OCc1ccccc1)=O)c1)c1F Chemical compound N#CC(CC1)CN1c(ccc(NC(OCc1ccccc1)=O)c1)c1F WSRDPIRQDIOHNS-UHFFFAOYSA-N 0.000 description 1
- SKUMURVVLMDCNF-UHFFFAOYSA-N [C-]#[N+]C1CCN(C2=C(F)C=C(N)C=C2)C1 Chemical compound [C-]#[N+]C1CCN(C2=C(F)C=C(N)C=C2)C1 SKUMURVVLMDCNF-UHFFFAOYSA-N 0.000 description 1
- YDBOUOUIMPGFEH-PYMCNQPYSA-N [C-]#[N+]C1CCN(C2=C(F)C=C(N3C[C@H](CNC(C)=O)OC3=O)C=C2)C1 Chemical compound [C-]#[N+]C1CCN(C2=C(F)C=C(N3C[C@H](CNC(C)=O)OC3=O)C=C2)C1 YDBOUOUIMPGFEH-PYMCNQPYSA-N 0.000 description 1
- BFDJJWAABQGBFU-YUZLPWPTSA-N [C-]#[N+]C1CCN(C2=C(F)C=C(N3C[C@H](CNC(C)=O)OC3=O)C=C2F)C1 Chemical compound [C-]#[N+]C1CCN(C2=C(F)C=C(N3C[C@H](CNC(C)=O)OC3=O)C=C2F)C1 BFDJJWAABQGBFU-YUZLPWPTSA-N 0.000 description 1
- ZZSUYUGMSTWMKU-UHFFFAOYSA-N [C-]#[N+]C1CCN(C2=C(F)C=C(NC(=O)OCC3=CC=CC=C3)C=C2)C1 Chemical compound [C-]#[N+]C1CCN(C2=C(F)C=C(NC(=O)OCC3=CC=CC=C3)C=C2)C1 ZZSUYUGMSTWMKU-UHFFFAOYSA-N 0.000 description 1
- BPKKGALWBQTWGZ-UHFFFAOYSA-N [C-]#[N+]C1CCN(C2=C(F)C=C([N+](=O)[O-])C=C2)C1 Chemical compound [C-]#[N+]C1CCN(C2=C(F)C=C([N+](=O)[O-])C=C2)C1 BPKKGALWBQTWGZ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- This invention is directed to antimicrobial oxazolidinone compounds which are active against Gram-positive and some Gram-negative bacteria, showing specifically a potent activity against linezolid-resistant (LNZ-R) strains of Gram-positive bacteria and more specifically against Gram-positive pathogenic respiratory bacteria.
- LNZ-R linezolid-resistant
- Oxazolidinones are Gram-positive antimicrobial agents. Oxazolidinones bind to the 50S subunit of the prokaryotic ribosome, preventing formation of the initiation complex for protein synthesis. This is a novel mode of action. Other protein synthesis inhibitors either block polypeptide extension or cause misreading of mRNA.
- Linezolid N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
- U.S. Pat. No. 5,688,792 is the first approved antimicrobial oxazolidinone for clinical use in the United States and elsewhere.
- the structural formula of linezolid is:
- MICs Linezolid minimal inhibitory concentrations
- Linezolid is indicated for the treatment of adult patients with the following infections: vancomycin-resistant Enterococcus faecium infections, including concurrent bacteremia; nosocomial pneumonia; complicated skin and skin structure infections; community-acquired pneumonia, including concurrent bacteremia; diabetic foot infections; and uncomplicated skin and skin structure infections.
- LNZ-R 432 Staphylococcus aureus
- ATCC 49247 Haemophylus influenzae
- ATCC 25285 Bacteroides fragilis
- HCl-78 Moraxella catarrhalis
- Enterococcus faecium LNZ-R
- oxazolidinones are also known for the treatment of microbial infections.
- WO 2005/054234 describes piperidino substituted phenyloxazolidinones for the treatment or prevention of Gram-positive or Gram negative microbial infections, including those which result from multi-resistant strains for instance, linezolid-resistant strains.
- the compounds of the present application are potent active antimicrobial agents showing a relevant activity against LNZ-R Gram-positive bacteria and more specifically against Gram-positive pathogenic respiratory bacteria.
- Differential characteristic properties of the compounds of the present invention versus linezolid indicate the potential use thereof in severe infections that cannot be properly treated with linezolid.
- the present invention refers to a compound of formula (I),
- R 1 and R 2 are radicals identical or different and are independently selected from hydrogen and fluorine;
- R 3 is a linear or branched (1-6C)alkyl group optionally substituted by a group selected from fluorine, hydroxy and OR 4 ; and R 4 is a linear or branched (1-6C)alkyl group.
- the present invention refers to a process for preparing a compound of formula (I) as defined in the first aspect of the invention in free or pharmaceutically acceptable salt, solvate, hydrate, or enantiomeric form that comprises:
- the present invention refers to a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of the compound of general formula (I) according to the first aspect of the invention, together with the appropriate amounts of pharmaceutical excipients or carriers.
- the present invention refers to a compound of formula (I) according to the first aspect of the invention, for use as a medicament.
- the present invention refers to the use of a compound of formula (I) according to the first aspect of the invention for the manufacture of a medicament for the treatment of bacterial infections in an animal or human.
- This aspect may also be formulated as a compound of formula (I) according to the first aspect of the invention for use in the treatment of bacterial infections.
- Another object of this invention is to provide novel methods to treat a mammal, including a human, suffering from a bacterial infection by administering a therapeutically effective amount of a compound of formula (I) in free or pharmaceutically acceptable salt, solvate, hydrate, or enantiomeric form.
- salts used herein encompasses any salt formed from organic and inorganic acids, such as hydrobromic, hydrochloric, phosphoric, nitric, sulfuric, acetic, adipic, aspartic, benzenesulfonic, benzoic, citric, ethanesulfonic, formic, fumaric, glutamic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, 1,5-naphthalendisulfonic, oxalic, pivalic, propionic, p-toluenesulfonic, succinic, tartaric acids, and the like, and any salt formed from organic and inorganic bases, such as the alkali metal and alkaline earth metal salts, especially the sodium and potassium salts, ammonium salts and salts of amines, including lower alkylated amines, such as methylamine, ethylamine, trimethylamine and the like,
- the present invention refers to a compound according to the first aspect of the invention wherein R 1 is fluorine, R 2 is selected from fluorine and hydrogen, and R 3 is methyl.
- the compound according to the first aspect of the invention is selected from the group consisting of:
- R 5 is benzyl
- R 6 is methyl
- X is bromine
- Inert solvents in step (i) are preferably aprotic solvents.
- Suitable aprotic solvents are polar ethers such as, for example, tetrahydrofuran, methyltetrahydrofuran, dioxane, tert-butylmethylether, or dimethoxyethylether, or amides such as, for example, dimethylformamide, or lactams such as, for example, N-methylpyrrolidone, and mixtures thereof.
- Suitable solvents are also mixtures of such aprotic solvents and alcohols such as, for example, methanol or ethanol.
- strong basic catalysts include hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, alkoxides, such as lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide, alkyllithiums such as tert-butyllithium, n-butyllithium, and methyllithium, dialkylamides such as lithium diisopropylamide, disilylamides such as lithium hexamethyldisilazide, potassium hexamethyldisilazide, and sodium hexamethyldisilazide, and hydrides such as lithium hydride, sodium hydride, and potassium hydride.
- hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide
- alkoxides such as lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide
- alkyllithiums such as tert-buty
- Useful processes for recovering the resultant compounds in step (ii) include conventional methods known to the person skilled in the art such as crystallization and chromatographic processes, resolution of racemic forms by chromatographic separation using a chiral stationary phase, and also processes involving fractional crystallization. This can, in particular, involve the separation of individual enantiomers, for example, diastereoisomeric salts formed with chiral acids, for example (+)-tartaric acid, ( ⁇ )-tartaric acid, or (+)-10-camphorsulfonic acid.
- the compounds of the present invention are useful antimicrobial agents, effective against a number of human and veterinary microorganisms.
- the compounds of the present invention are effective against an infection produced by linezolid-resistant strain.
- the compounds of the present invention are effective against an infection produced by Gram-positive pathogenic respiratory bacteria.
- Some non limitative examples of these microorganisms are Staphylococcus aureus, Streptococcus pneumoniae, Haemophylus influenzae, Bacteroides fragilis, Moraxella catarrhalis , and Enterococcus faecium .
- the compounds of the present invention are more active against linezolid-resistant strains than both linezolid and the closest structurally substituted oxazolidinone of the state of the art. They are also more active against Gram-positive pathogenic respiratory bacteria than both linezolid and the closest structurally substituted oxazolidinone of the state of the art.
- the compounds of the present invention can be normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
- compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, parenteral, inhalatory, rectal, transdermal or topical administration.
- the compounds of this invention may be formulated by means known in the art in the form of, for example, tablets, capsules, syrups, aqueous or oily solutions or suspensions, emulsions, dispersible powders, inhalatory solutions, suppositories, ointments, creams, drops and sterile aqueous or oily solutions or suspensions for injection and the like.
- the pharmaceutical compositions may contain flavoring agents, sweeteners, etc.
- compositions typically contain from 1 to 40%, preferably 1 to 10% by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents, solvents and the like.
- the compounds of formula (I) are administered in an amount of 0.1 to 100 mg/kg of body weight/day, preferably 1 to 50 mg/kg of body weight/day.
- the compounds and compositions of the present invention are useful in the treatment of conditions such as nosocomial pneumoniae , community acquired pneumoniae , caused by methicillin-resistant Staphylococcus aureus (MRSA), including concurrent bacteremia, penicillin resistance and sensitive Streptococcus pneumoniae , diabetic foot infections and skin and skin structure infections, and all other infections caused by bacteria sensitive to the compounds described in the invention.
- MRSA methicillin-resistant Staphylococcus aureus
- the compounds of the present invention are effective against a number of human or animal pathogens, clinical isolates, including vancomycin-resistant organisms, methicillin-resistant organisms, and LNZ-R organisms.
- compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof for antimicrobial use in humans or animals are listed:
- Buffers pharmaceutically acceptable co-solvents such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents, may be used to aid formulation.
- the above formulations may be prepared by well-known conventional procedures in the pharmaceutical art.
- the tablets 1-3 may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
- MICs were determined by using a standard micro dilution method according to The National Committee for Clinical Laboratory Standards (NCCLS), 5th Approved standard M7-A5, 2001, Wayne, Pa., USA. All compounds were tested against Gram-positive and Gram-negative bacteria showing relevant different susceptibility and resistance specifications. The used micro organisms were selected from laboratory reference bacteria and from clinical isolates. The tested concentrations were double dilutions from 0.06 ⁇ g/mL to 128 ⁇ g/mL in 96-well micro titter plates.
- NCCLS National Committee for Clinical Laboratory Standards
- MICs were determined in the Brucella Blood medium supplemented for the anaerobic strains, and in the Mueller-Hinton culture medium (cation-adjusted) for the aerobic bacteria.
- the tested compounds were dissolved in DMSO, and were diluted as far as 2560 ⁇ g/mL with the different media according to the specific requirements for each group of strains.
- the 96-well sealed micro titter plates containing bacteria were incubated in different laboratory conditions depending on the nature of the microorganism.
- the aerobic bacteria were incubated during 16-24 h at 35° C. and the so-called fastidious bacteria, such as M. catarrhalis and S. pneumoniae , during 20-24 h at 35° C. in a microaerobiotic atmosphere containing 5% CO 2 (Anaerocult C, MERCK).
- the results of these tests are given in Table 1.
- MIC values of table 1 show that less concentration of compounds of example 1 and 2 is required to inhibit the bacterial grown than for linezolid. Thus, the previous results show that the compounds of the present invention are more active than against linezolid-resistant strains.
- This example compares the antibacterial activity against linezolid-resistant strains and Gram positive pathogenic respiratory bacteria of the compound of example 1 of the present invention with the reference compound of example 5.
- Compound of example 5 is the structurally closest oxazolidinone of the state of the art, where the pyrrolidine ring contains a hydroxyl moiety instead of the cyano group.
- MICs were determined by the same methods described in example 4 and the tested samples were also prepared as shown in example 4.
- MIC values of Table 2 show that less concentration of the compound of example 1 is required to inhibit the bacterial grown in respect to compound of example 5.
- compound of example 1 is much more effective as an antibacterial agent including linezolid-resistant strains and Gram-positive pathogenic respiratory bacteria in all antibacterial species tested.
Abstract
Description
- This invention is directed to antimicrobial oxazolidinone compounds which are active against Gram-positive and some Gram-negative bacteria, showing specifically a potent activity against linezolid-resistant (LNZ-R) strains of Gram-positive bacteria and more specifically against Gram-positive pathogenic respiratory bacteria.
- Oxazolidinones are Gram-positive antimicrobial agents. Oxazolidinones bind to the 50S subunit of the prokaryotic ribosome, preventing formation of the initiation complex for protein synthesis. This is a novel mode of action. Other protein synthesis inhibitors either block polypeptide extension or cause misreading of mRNA. Linezolid (N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide), U.S. Pat. No. 5,688,792, is the first approved antimicrobial oxazolidinone for clinical use in the United States and elsewhere. The structural formula of linezolid is:
- Linezolid minimal inhibitory concentrations (MICs) vary slightly with the test mode, laboratory, and significance attributed to thin hazes of bacterial survival, but all workers find that the susceptibility distributions are narrow and unimodal with MIC values between 0.5 and 4 μg/mL for streptococci, enterococci and staphylococci. Full activity is retained against Gram-positive cocci resistant to other antibiotics, including methicillin-resistant staphylococci and vancomycin-resistant enterococci. MICs are 2-8 μg/mL for Moraxella, Pasteurella and Bacteroides spp. but other Gram-negative bacteria are resistant as a result of endogenous of activity as well as the intake presented by Gram-negative bacteria outer membrane cell. Linezolid is indicated for the treatment of adult patients with the following infections: vancomycin-resistant Enterococcus faecium infections, including concurrent bacteremia; nosocomial pneumonia; complicated skin and skin structure infections; community-acquired pneumonia, including concurrent bacteremia; diabetic foot infections; and uncomplicated skin and skin structure infections.
- Unfortunately, some Gram-positive bacteria such as Staphylococcus aureus (LNZ-R 432), Haemophylus influenzae (ATCC 49247), Bacteroides fragilis (ATCC 25285), Moraxella catarrhalis (HCl-78), and Enterococcus faecium (LNZ-R) show an important resistance to linezolid.
- Other oxazolidinones are also known for the treatment of microbial infections. For instance, WO 2005/054234 describes piperidino substituted phenyloxazolidinones for the treatment or prevention of Gram-positive or Gram negative microbial infections, including those which result from multi-resistant strains for instance, linezolid-resistant strains.
- International patent application WO 96/13502 discloses phenyl oxazolidinones having a multisubstituted azetidinyl or pyrrolidinyl moiety. These compounds are useful antimicrobial agents, which are effective against a number of human and veterinary pathogens, particularly aerobic gram-positive bacteria, including some activity against multiply-resistant staphylococci, enterococci and streptococci.
- Although there are known some oxazolidinones which have some activity against linezolid-resistant Gram-positive bacteria, there continue being the need of new oxazolidinone compounds active against these strains, since some of them are the origin of severe and sometimes fatal infections such as sepsis and septic shock. There is also a need for improved agents against Gram-positive pathogenic respiratory bacteria, like Streptococcus pneumoniae, Haemophylus influenzae, and Moraxella catarrhalis.
- Surprisingly the compounds of the present application are potent active antimicrobial agents showing a relevant activity against LNZ-R Gram-positive bacteria and more specifically against Gram-positive pathogenic respiratory bacteria. Differential characteristic properties of the compounds of the present invention versus linezolid indicate the potential use thereof in severe infections that cannot be properly treated with linezolid.
- In a first aspect the present invention refers to a compound of formula (I),
- in free or pharmaceutically acceptable salt, solvate, hydrate, or enantiomeric form, wherein:
- R1 and R2 are radicals identical or different and are independently selected from hydrogen and fluorine;
- R3 is a linear or branched (1-6C)alkyl group optionally substituted by a group selected from fluorine, hydroxy and OR4; and
R4 is a linear or branched (1-6C)alkyl group. - In a second aspect the present invention refers to a process for preparing a compound of formula (I) as defined in the first aspect of the invention in free or pharmaceutically acceptable salt, solvate, hydrate, or enantiomeric form that comprises:
- (i) reacting an intermediate of formula (II),
-
- wherein R1 and R2 are as defined above and R5 is selected from linear or branched (1-6C)alkyl and benzyl optionally phenyl-substituted by up to three linear or branched (1-6C)alkyl groups, with an intermediate of formula (III),
-
- wherein R3 is as defined above, R6 is a linear or branched (1-6C)alkyl group, and X is a halogen atom; and
- (ii) recovering the resultant compound of formula (I) in free or pharmaceutically acceptable salt, solvate, hydrate, or enantiomeric form.
- In a third aspect the present invention refers to a pharmaceutical composition comprising a therapeutically effective amount of the compound of general formula (I) according to the first aspect of the invention, together with the appropriate amounts of pharmaceutical excipients or carriers.
- In a fourth aspect the present invention refers to a compound of formula (I) according to the first aspect of the invention, for use as a medicament.
- In an fifth aspect the present invention refers to the use of a compound of formula (I) according to the first aspect of the invention for the manufacture of a medicament for the treatment of bacterial infections in an animal or human.
- This aspect may also be formulated as a compound of formula (I) according to the first aspect of the invention for use in the treatment of bacterial infections.
- Another object of this invention is to provide novel methods to treat a mammal, including a human, suffering from a bacterial infection by administering a therapeutically effective amount of a compound of formula (I) in free or pharmaceutically acceptable salt, solvate, hydrate, or enantiomeric form.
- The term “pharmaceutically acceptable salts” used herein encompasses any salt formed from organic and inorganic acids, such as hydrobromic, hydrochloric, phosphoric, nitric, sulfuric, acetic, adipic, aspartic, benzenesulfonic, benzoic, citric, ethanesulfonic, formic, fumaric, glutamic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, 1,5-naphthalendisulfonic, oxalic, pivalic, propionic, p-toluenesulfonic, succinic, tartaric acids, and the like, and any salt formed from organic and inorganic bases, such as the alkali metal and alkaline earth metal salts, especially the sodium and potassium salts, ammonium salts and salts of amines, including lower alkylated amines, such as methylamine, ethylamine, trimethylamine and the like, hydroxyloweralkylamines, such as ethanolamine and diethanolamine, and heterocyclic amines, such as morpholine and piperazine.
- In a preferred embodiment, the present invention refers to a compound according to the first aspect of the invention wherein R1 is fluorine, R2 is selected from fluorine and hydrogen, and R3 is methyl.
- Preferably, the compound according to the first aspect of the invention is selected from the group consisting of:
- N-{(5S)-3-[3-fluoro-4-(3-cyanopyrrolidin-1-yl)phenyl]-2-oxo-5-oxazolidinylmethyl}acetamide;
- N-{(5S)-3-[3,5-difluoro-4-(3-cyanopyrrolidin-1-yl)phenyl]-2-oxo-5-oxazolidinylmethyl}acetamide;
- N-{(5S)-3-[3-fluoro-4-(3(R)-cyanopyrrolidin-1-yl)phenyl]-2-oxo-5-oxazolidinylmethyl}acetamide;
- N-{(5S)-3-[3,5-difluoro-4-(3(R)-cyanopyrrolidin-1-yl)phenyl]-2-oxo-5-oxazolidinylmethyl}acetamide;
- N-{(5S)-3-[3-fluoro-4-(3(S)-cyanopyrrolidin-1-yl)phenyl]-2-oxo-5-oxazolidinylmethyl}acetamide; and
- N-{(5S)-3-[3,5-difluoro-4-(3(S)-cyanopyrrolidin-1-yl)phenyl]-2-oxo-5-oxazolidinylmethyl}acetamide.
The compounds of general formula (I) may be prepared by - (i) reacting an intermediate of formula (II),
-
- wherein R1 and R2 are as defined above and R5 is selected from linear or branched (1-6C)alkyl and benzyl optionally phenyl-substituted by up to three linear or branched (1-6C)alkyl groups, with an intermediate of formula (III),
-
- wherein R3 is as defined above, R6 is a linear or branched (1-6C)alkyl group, and X is a halogen atom, in an inert solvent and in the presence of a strong basic catalyst; and
- (ii) recovering the resultant compound of formula (I) in free or pharmaceutically acceptable salt, solvate, hydrate, or enantiomeric form.
- Preferably R5 is benzyl, R6 is methyl and X is bromine.
- Inert solvents in step (i) are preferably aprotic solvents. Suitable aprotic solvents are polar ethers such as, for example, tetrahydrofuran, methyltetrahydrofuran, dioxane, tert-butylmethylether, or dimethoxyethylether, or amides such as, for example, dimethylformamide, or lactams such as, for example, N-methylpyrrolidone, and mixtures thereof. Suitable solvents are also mixtures of such aprotic solvents and alcohols such as, for example, methanol or ethanol.
- Examples of strong basic catalysts include hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, alkoxides, such as lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide, alkyllithiums such as tert-butyllithium, n-butyllithium, and methyllithium, dialkylamides such as lithium diisopropylamide, disilylamides such as lithium hexamethyldisilazide, potassium hexamethyldisilazide, and sodium hexamethyldisilazide, and hydrides such as lithium hydride, sodium hydride, and potassium hydride.
- Useful processes for recovering the resultant compounds in step (ii) include conventional methods known to the person skilled in the art such as crystallization and chromatographic processes, resolution of racemic forms by chromatographic separation using a chiral stationary phase, and also processes involving fractional crystallization. This can, in particular, involve the separation of individual enantiomers, for example, diastereoisomeric salts formed with chiral acids, for example (+)-tartaric acid, (−)-tartaric acid, or (+)-10-camphorsulfonic acid.
- The compounds of the present invention are useful antimicrobial agents, effective against a number of human and veterinary microorganisms. In a preferred embodiment, the compounds of the present invention are effective against an infection produced by linezolid-resistant strain. In another preferred embodiment, the compounds of the present invention are effective against an infection produced by Gram-positive pathogenic respiratory bacteria. Some non limitative examples of these microorganisms are Staphylococcus aureus, Streptococcus pneumoniae, Haemophylus influenzae, Bacteroides fragilis, Moraxella catarrhalis, and Enterococcus faecium. As it is illustrated in the Examples 4 and 6, the compounds of the present invention are more active against linezolid-resistant strains than both linezolid and the closest structurally substituted oxazolidinone of the state of the art. They are also more active against Gram-positive pathogenic respiratory bacteria than both linezolid and the closest structurally substituted oxazolidinone of the state of the art.
- The compounds of the present invention can be normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
- The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, parenteral, inhalatory, rectal, transdermal or topical administration. For these purposes the compounds of this invention may be formulated by means known in the art in the form of, for example, tablets, capsules, syrups, aqueous or oily solutions or suspensions, emulsions, dispersible powders, inhalatory solutions, suppositories, ointments, creams, drops and sterile aqueous or oily solutions or suspensions for injection and the like. The pharmaceutical compositions may contain flavoring agents, sweeteners, etc. in suitable solid or liquid carriers or diluents, or in a suitable sterile media to form suspensions or solutions suitable for intravenous, subcutaneous or intramuscular injection. Such compositions typically contain from 1 to 40%, preferably 1 to 10% by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents, solvents and the like.
- The compounds of formula (I) are administered in an amount of 0.1 to 100 mg/kg of body weight/day, preferably 1 to 50 mg/kg of body weight/day. The compounds and compositions of the present invention are useful in the treatment of conditions such as nosocomial pneumoniae, community acquired pneumoniae, caused by methicillin-resistant Staphylococcus aureus (MRSA), including concurrent bacteremia, penicillin resistance and sensitive Streptococcus pneumoniae, diabetic foot infections and skin and skin structure infections, and all other infections caused by bacteria sensitive to the compounds described in the invention. The compounds of the present invention are effective against a number of human or animal pathogens, clinical isolates, including vancomycin-resistant organisms, methicillin-resistant organisms, and LNZ-R organisms.
- Throughout the description and claims the word “comprise” and variations of the word, such as “comprising”, are not intended to exclude other technical features, additives, components, or steps. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples are provided by way of illustration, and are not intended to be limiting of the present invention.
-
- 3-Carbonitrile pyrrolidine (133 mg) and potassium carbonate (268 mg) were dissolved in dimethylformamide (1 mL), and 3,4-difluoronitrobenzene (198 mg) added. The mixture was stirred at room temperature under nitrogen for 20 hours. Dichloromethane (DCM) was added to the reaction mixture and washed with water, brine and dried (magnesium sulfate). The residue was purified by column chromatography (11 g silica gel, DCM) to get 249 mg of title product (Yield=80%).
- HPLC (t, %): 8.04 min, 100%.
- MS (ESI) m/z=236 (M+1)
- 1H NMR (400 MHz, ppm, CDCl3): 2.38 (2H, m), 3.27 (1H, m), 3.67 (1H, m), 3.77 (1H, m), 3.89 (2H, m), 6.57 (1H, t, J=9.2 Hz), 7.92 (2H, m)
-
- 3-Fluoro-4-[3-cyanopyrrolidinyl]nitrobenzene (220 mg) was dissolved in ethanol (20 mL) and treated with tin chloride (SnCl2.2H2O, 1.5 g). The mixture was stirred and heated to reflux under nitrogen for 6 hours. Aqueous sodium bicarbonate and DCM were added, the organic layer separated and the aqueous layer extracted with DCM. The combined organic layers were dried and concentrated to give title product (141 mg. Yield=73%).
- HPLC (t, %): 6.41 min, 100%.
- MS (ESI) m/z=206 (M+1)
- 1H NMR (400 MHz, ppm, CDCl3): 2.68 (2H, m), 3.21 (1H, m), 3.30 (2H, m), 3.35 (1H, m), 3.49 (1H, m), 6.45 (2H, m), 6.59 (1H, t, J=8 Hz)
-
- 3-Fluoro-4-[3-cyanopyrrolidinyl]phenylamine (120 mg) was dissolved in acetone (4 mL) and cooled to 0° C. Sodium hydrogen carbonate (196 mg, 4 eq) in water (2 mL) was added, followed by benzyl chloroformate (199 mg, 2 eq) over 30 minutes. The mixture was stirred and the temperature allowed to rise to ambient over 3 hours. DCM was added and the organic layer separated, and washed with water and brine. The combined organic layers were dried over magnesium sulfate and concentrated. The residue was purified by column chromatography (10 gr silica gel) eluting with DCM and DCM/MeOH 98/2 to give 185 mg of title product (Yield=93%).
- HPLC (t, %): 9.06 min, 100%.
- MS (ESI) m/z=340 (M+1)
- 1H NMR (400 MHz, ppm, CDCl3): 2.31 (2H, m), 3.17 (1H, m), 3.43 (2H, m), 3.54 (1H, m), 3.67 (1H, m), 5.17 (2H,$), 6.50 (1H, m), 6.61 (1H, t, J=9 Hz), 6.90 (1H, m), 7.38 (5H, m)
-
- To a solution of 175 mg of 3-fluoro-4-[3-cyanopyrrolidinyl]-phenylcarbamic acid benzyl ester in 350 μL of dimethylformamide (DMF) was added 1.5 mL of a solution of 1M of lithium tert-butoxide in tetrahydrofuran (THF) and stirred at room temperature for 30 minutes. 42 μL of methanol and a solution of 246 mg of (S)—N-(3-bromo-2-acetoxypropyl)acetamide in 350 μl of DMF were added and allowed to stand at room temperature for two days at which point HPLC showed a 30% conversion. The same amount of lithium tert-butoxide in THF, methanol and (S)—N-(3-bromo-2-acetoxypropyl)acetamide were added and reaction mixture stirred at room temperature for two days more. Saturated aqueous ammonium chloride was added to the reaction solution and the separated organic layer was washed with water, brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (DCM, methanol in increasing polarity) to afford 113 mg of the title compound (Yield=63%).
- HPLC (t, %): 6.58 min, 100%.
- MS (ESI) m/z=347 (M+1)
- 1H NMR (400 MHz, ppm, DMSO): 2.16 (1H, m), 2.30 (1H, m), 3.38 (4H, m), 3.66 (1H, dd, J=6.8, 8.8 Hz), 4.05 (1H, t, J=9 Hz), 4.67 (1H, m), 6.83 (1H, t, J=9 Hz), 7.11 (1H, dd, J=2.4, 9 Hz), 7.43 (1H, dd, J=2.8, 16 Hz)
-
- It was obtained in a similar way than compound of Example 1, starting from alkylation of 3,4,5-trifluoronitrobenzene with 3-carbonitrile pyrrolidine.
- HPLC (t, %): 6.94 min, 92%.
- MS (ESI) m/z=365 (M+1)
- 1H NMR (400 MHz, ppm, CDCl3): 1.82 (3H, s), 2.25 (2H, m), 3.13 (1H, q, J=7.2 Hz), 3.58 (7H, m), 3.96 (1H, t, J=9.2 Hz), 4.75 (1H, m), 6.04 (1H, NH), 7.06 (2H, d, J=10.8 Hz)
- The following illustrate representative pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof for antimicrobial use in humans or animals:
-
Tablet 1 mg/tablet Active ingredient 100 Lactose 179 Croscarmellose sodium 12 Polyvinylpyrrolidone 6 Magnesium stearate 3 -
Tablet 2 mg/tablet Active ingredient 50 Lactose 229 Croscarmellose sodium 12 Polyvinylpyrrolidone 6 Magnesium stearate 3 -
Tablet 3 mg/tablet Active ingredient 1 Lactose 92 Croscarmellose sodium 4 Polyvinylpyrrolidone 2 Magnesium stearate 1 -
Capsule mg/capsule Active ingredient 10 Lactose 389 Croscarmellose sodium 100 Magnesium stearate 1 -
Injection 50 mg/mL Active ingredient 5.0% w/v Isotonic aqueous solution to 100% - Buffers, pharmaceutically acceptable co-solvents such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents, may be used to aid formulation.
- The above formulations may be prepared by well-known conventional procedures in the pharmaceutical art. The tablets 1-3 may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
- MICs were determined by using a standard micro dilution method according to The National Committee for Clinical Laboratory Standards (NCCLS), 5th Approved standard M7-A5, 2001, Wayne, Pa., USA. All compounds were tested against Gram-positive and Gram-negative bacteria showing relevant different susceptibility and resistance specifications. The used micro organisms were selected from laboratory reference bacteria and from clinical isolates. The tested concentrations were double dilutions from 0.06 μg/mL to 128 μg/mL in 96-well micro titter plates.
- MICs were determined in the Brucella Blood medium supplemented for the anaerobic strains, and in the Mueller-Hinton culture medium (cation-adjusted) for the aerobic bacteria.
- The tested compounds were dissolved in DMSO, and were diluted as far as 2560 μg/mL with the different media according to the specific requirements for each group of strains. The 96-well sealed micro titter plates containing bacteria were incubated in different laboratory conditions depending on the nature of the microorganism. Thus, the aerobic bacteria were incubated during 16-24 h at 35° C. and the so-called fastidious bacteria, such as M. catarrhalis and S. pneumoniae, during 20-24 h at 35° C. in a microaerobiotic atmosphere containing 5% CO2 (Anaerocult C, MERCK). The results of these tests are given in Table 1.
-
TABLE 1 Ex. 1 Ex. 2 Linezolid S. aureus 0.5 0.25 1.00 ATCC25923 MS S. pneumoniae 0.25 0.125 1.00 ATCC49619 PR E. faecium 0.25 0.125 0.50 ATCC51559 MDR S. aureus LNZ-R 4 64 16-32 432 H. influenzae 4 2 16.00 ATCC49247 B. fragilis sp. 0.5 0.125 2.00 fragilis ATCC25285 Moraxella 2 0.25 2.00 catarrhalis HCI-78 E. faecium LNZ-R 8 4 64.00 LR-4 - MIC values of table 1 show that less concentration of compounds of example 1 and 2 is required to inhibit the bacterial grown than for linezolid. Thus, the previous results show that the compounds of the present invention are more active than against linezolid-resistant strains.
-
- It was obtained according to the process disclosed in the example 10 page 50 of the International patent application WO 9613502.
- This example compares the antibacterial activity against linezolid-resistant strains and Gram positive pathogenic respiratory bacteria of the compound of example 1 of the present invention with the reference compound of example 5. Compound of example 5 is the structurally closest oxazolidinone of the state of the art, where the pyrrolidine ring contains a hydroxyl moiety instead of the cyano group.
- In order to compare the antibacterial activity of both compounds, MICs were determined by the same methods described in example 4 and the tested samples were also prepared as shown in example 4.
- The results are summarized in Table 2.
-
TABLE 2 Ex. 1 (μg/mL) Ex. 5 (μg/mL) S. aureus clinical strain cfr. 4 16 methylase S. aureus 1199 1 2 S. aureus 199B 1 2 MRSE 0.25 1 MRSE-128 8 32 S. Haemolyticus 8 32 E. faecalis ECFL-1 0.125 2 E. faecalis ECFL-1-128 32 64 E. faecalis ECFL-2 1 4 E. faecium ECFM-1 0.5 2 E. faecium ECFM-1-128 32 64 E. faecium ECFM-2 0.5 2 Geom. Mean MIC Staphyl. 0.4 1.2 Geom. Mean MIC Enteroc. 0.3 1.7 Geom. Mean MIC Gram+ 0.3 1.4 S. aureus ATCC33591 in vivo 0.25 2 S. pneumoniae ATCC6303 in vivo 0.25 0.5 S. aureus ATCC25923 MS 0.5 2 S. aureus ATCC43300 MR 0.5 1 S. aureus 1199B NorA overE 0.5 1 S. epidermidis ATCC12228 MR 0.25 1 S. pneumoniae ATCC49619 PR 0.25 1 E. faecalis ATCC29212 0.25 2 E. faecalis ATCC51575 MDR 0.25 2 E. faecium ATCC10541 0.25 2 E. faecium ATCC51559 MDR 0.25 1 E. faecium LNZ-R LR-4 8 32 E. coli TG1 32 64 E. coli KAM-3 1 4 - MIC values of Table 2 show that less concentration of the compound of example 1 is required to inhibit the bacterial grown in respect to compound of example 5.
- Therefore, compound of example 1 is much more effective as an antibacterial agent including linezolid-resistant strains and Gram-positive pathogenic respiratory bacteria in all antibacterial species tested.
Claims (17)
1. A compound of formula (I),
in free or pharmaceutically acceptable salt, solvate, hydrate, or enantiomeric form, wherein:
R1 and R2 are radicals identical or different and are independently selected from the group consisting of hydrogen and fluorine;
R3 is a linear or branched (1-6C)alkyl group optionally substituted by a group selected from the group consisting of fluorine, hydroxy and OR4; and
R4 is a linear or branched (1-6C)alkyl group.
2. The compound according to claim 1 , wherein R1 is fluorine.
3. (canceled)
4. The compound according to claim 1 , wherein R3 is methyl.
5. The compound as claimed in any of the preceding claims, which is selected from the group consisting of:
N-{(5S)-3-[3-fluoro-4-(3-cyanopyrrolidin-1-yl)phenyl]-2-oxo-5-oxazolidinylmethyl}acetamide;
N-{(5S)-3-[3,5-difluoro-4-(3-cyanopyrrolidin-1-yl)phenyl]-2-oxo-5-oxazolidinylmethyl}acetamide;
N-{(5S)-3-[3-fluoro-4-(3(R)-cyanopyrrolidin-1-yl)phenyl]-2-oxo-5-oxazolidinylmethyl}acetamide;
N-{(5S)-3-[3,5-difluoro-4-(3(R)-cyanopyrrolidin-1-yl)phenyl]-2-oxo-5-oxazolidinylmethyl}acetamide;
N-{(5S)-3-[3-fluoro-4-(3(S)-cyanopyrrolidin-1-yl)phenyl]-2-oxo-5-oxazolidinylmethyl}acetamide; and
N-{(5S)-3-[3,5-difluoro-4-(3(S)-cyanopyrrolidin-1-yl)phenyl]-2-oxo-5-oxazolidinylmethyl}acetamide.
6. A process for preparing a compound of formula (I) in free or pharmaceutically acceptable salt, solvate, hydrate, or enantiomeric form that comprises:
(i) reacting an intermediate of formula (II),
wherein R1 and R2 are radicals identical or different and are independently selected from the group consisting of hydrogen and fluorine, and R5 is selected from the group consisting of linear or branched (1-6C)alkyl and benzyl optionally phenyl-substituted by up to three linear or branched (1-6C)alkyl groups, with an intermediate of formula (III),
wherein R3 is a linear or branched (1-6C)alkyl group optionally substituted by a group selected from the group consisting of fluorine, hydroxy and OR4, R6 is a linear or branched (1-6C)alkyl group, and X is a halogen atom; and
(ii) recovering the resultant compound of formula (I) in free or pharmaceutically acceptable salt, solvate, hydrate, or enantiomeric form.
7. The process of claim 6 wherein R5 is benzyl, R6 is methyl and X is bromine.
8. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) as defined in claim 1 , together with the appropriate amounts of pharmaceutical excipients or carriers.
9-13. (canceled)
14. A method for treating bacterial infections, which comprises administering a compounds of formula (I) as defined in claim 1 , to an animal or human in need thereof for the treatment of bacterial infections.
15. The method of claim 14 , wherein said compound is administered to an animal.
16. The method of claim 14 , wherein said compound is administered to a mammal.
17. The method of claim 14 , wherein said compound is administered to a human.
18. The method according to claim 14 , wherein the bacterial infection is an infection produced by linezolid-resistant strain.
19. The method according to claim 14 , wherein the bacterial infection is an infection produced by Gram-positive pathogenic respiratory bacteria.
20. The method of claim 14 , wherein the compound is administered by oral, parenteral, inhalatory, rectal, transdermal or topical administration.
21. The method of claim 14 , wherein the compound is administered in an amount of 0.1 to 100 mg/kg body weight/day.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP08159446A EP2141161A1 (en) | 2008-07-01 | 2008-07-01 | 3-cyanopyrrolidinyl-phenyl-oxazolidinones as antibacterial agents |
EP08159446.7 | 2008-07-01 | ||
PCT/EP2009/058125 WO2010000703A1 (en) | 2008-07-01 | 2009-06-29 | 3-cyanopyrrolidinyl-phenyl-oxazolidinones as antibacterial agents |
Publications (1)
Publication Number | Publication Date |
---|---|
US20110152333A1 true US20110152333A1 (en) | 2011-06-23 |
Family
ID=40010598
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/002,097 Abandoned US20110152333A1 (en) | 2008-07-01 | 2009-06-29 | 3-cyanopyrrolidinyl-phenyl-oxazolidinones as antibacterial agents |
Country Status (23)
Country | Link |
---|---|
US (1) | US20110152333A1 (en) |
EP (2) | EP2141161A1 (en) |
JP (1) | JP2011526589A (en) |
KR (1) | KR20110036601A (en) |
CN (1) | CN102112471A (en) |
AR (1) | AR072389A1 (en) |
AT (1) | ATE541842T1 (en) |
AU (1) | AU2009265790A1 (en) |
BR (1) | BRPI0913842A2 (en) |
CA (1) | CA2729491A1 (en) |
CL (2) | CL2009001493A1 (en) |
CY (1) | CY1112684T1 (en) |
DK (1) | DK2321306T3 (en) |
ES (1) | ES2381155T3 (en) |
MX (1) | MX2011000141A (en) |
PE (1) | PE20110161A1 (en) |
PL (1) | PL2321306T3 (en) |
PT (1) | PT2321306E (en) |
RU (1) | RU2011103485A (en) |
SI (1) | SI2321306T1 (en) |
TW (1) | TW201006828A (en) |
UY (1) | UY31953A (en) |
WO (1) | WO2010000703A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101128029B1 (en) | 2010-03-08 | 2012-03-29 | 주식회사 레고켐 바이오사이언스 | Method for preparing of R-3-3-fluoro-4-1-methyl-5,6-dihydro-1,2,4-triazin-41H-ylphenyl-5-substituted methyloxazolidin-2-one derivatives |
ES2699001T3 (en) * | 2013-11-08 | 2019-02-06 | Lee Pharma Ltd | New oxazolidinone antibacterial compound |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996013502A1 (en) * | 1994-10-26 | 1996-05-09 | Pharmacia & Upjohn Company | Phenyloxazolidinone antimicrobials |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5688792A (en) | 1994-08-16 | 1997-11-18 | Pharmacia & Upjohn Company | Substituted oxazine and thiazine oxazolidinone antimicrobials |
US7687627B2 (en) * | 2003-09-08 | 2010-03-30 | Wockhardt Limited | Substituted piperidino phenyloxazolidinones having antimicrobial activity with improved in vivo efficacy |
-
2008
- 2008-07-01 EP EP08159446A patent/EP2141161A1/en not_active Withdrawn
-
2009
- 2009-06-26 CL CL2009001493A patent/CL2009001493A1/en unknown
- 2009-06-29 AT AT09772403T patent/ATE541842T1/en active
- 2009-06-29 KR KR1020117002584A patent/KR20110036601A/en not_active Application Discontinuation
- 2009-06-29 PT PT09772403T patent/PT2321306E/en unknown
- 2009-06-29 CA CA2729491A patent/CA2729491A1/en not_active Abandoned
- 2009-06-29 JP JP2011515413A patent/JP2011526589A/en active Pending
- 2009-06-29 PL PL09772403T patent/PL2321306T3/en unknown
- 2009-06-29 TW TW098121757A patent/TW201006828A/en unknown
- 2009-06-29 ES ES09772403T patent/ES2381155T3/en active Active
- 2009-06-29 MX MX2011000141A patent/MX2011000141A/en not_active Application Discontinuation
- 2009-06-29 EP EP09772403A patent/EP2321306B1/en not_active Not-in-force
- 2009-06-29 CN CN2009801301840A patent/CN102112471A/en active Pending
- 2009-06-29 RU RU2011103485/04A patent/RU2011103485A/en not_active Application Discontinuation
- 2009-06-29 AU AU2009265790A patent/AU2009265790A1/en not_active Abandoned
- 2009-06-29 PE PE2010001214A patent/PE20110161A1/en not_active Application Discontinuation
- 2009-06-29 BR BRPI0913842A patent/BRPI0913842A2/en not_active IP Right Cessation
- 2009-06-29 US US13/002,097 patent/US20110152333A1/en not_active Abandoned
- 2009-06-29 AR ARP090102398A patent/AR072389A1/en unknown
- 2009-06-29 WO PCT/EP2009/058125 patent/WO2010000703A1/en active Application Filing
- 2009-06-29 DK DK09772403.3T patent/DK2321306T3/en active
- 2009-06-29 SI SI200930234T patent/SI2321306T1/en unknown
- 2009-07-01 UY UY0001031953A patent/UY31953A/en unknown
-
2010
- 2010-12-28 CL CL2010001589A patent/CL2010001589A1/en unknown
-
2012
- 2012-04-12 CY CY20121100363T patent/CY1112684T1/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996013502A1 (en) * | 1994-10-26 | 1996-05-09 | Pharmacia & Upjohn Company | Phenyloxazolidinone antimicrobials |
Also Published As
Publication number | Publication date |
---|---|
ES2381155T3 (en) | 2012-05-23 |
CL2010001589A1 (en) | 2011-11-11 |
KR20110036601A (en) | 2011-04-07 |
CY1112684T1 (en) | 2016-02-10 |
AU2009265790A1 (en) | 2010-01-07 |
PE20110161A1 (en) | 2011-03-15 |
CA2729491A1 (en) | 2010-01-07 |
PT2321306E (en) | 2012-04-13 |
EP2141161A1 (en) | 2010-01-06 |
EP2321306B1 (en) | 2012-01-18 |
JP2011526589A (en) | 2011-10-13 |
DK2321306T3 (en) | 2012-04-10 |
PL2321306T3 (en) | 2012-06-29 |
SI2321306T1 (en) | 2012-05-31 |
RU2011103485A (en) | 2012-08-10 |
CL2009001493A1 (en) | 2009-12-11 |
ATE541842T1 (en) | 2012-02-15 |
EP2321306A1 (en) | 2011-05-18 |
MX2011000141A (en) | 2011-04-05 |
WO2010000703A1 (en) | 2010-01-07 |
UY31953A (en) | 2010-01-29 |
CN102112471A (en) | 2011-06-29 |
TW201006828A (en) | 2010-02-16 |
BRPI0913842A2 (en) | 2015-10-20 |
AR072389A1 (en) | 2010-08-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20040242591A1 (en) | Oxazolidinone derivatives as pontential antimicrobials | |
EP1745784A1 (en) | Oxazolidinone derivatives and use thereof as antibiotics | |
US20060293307A1 (en) | Oxazolidinone derivatives as antimicrobials | |
JP5662940B2 (en) | New antimicrobial agents | |
EP2321306B1 (en) | 3-cyanopyrrolidinyl-phenyl-oxazolidinones as antibacterial agents | |
KR101271224B1 (en) | Oxazolidinone derivatives containing new bicyclic group, having antibacterial activity, and preparation method thereof | |
EP2324016B1 (en) | 3-(n-heterocyclyl)-pyrrolidinyl-phenyl-oxazolidinones as antibacterial agents | |
US20080214565A1 (en) | Oxazolidinone Derivatives as Antimicrobials | |
EP2072514A1 (en) | 1(2)H-tetrazol-5-yl-phenyl-oxazolidinones as antibacterial agents | |
KR100980681B1 (en) | Novel oxazolidinone derivatives with difluorophenyl derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition for antibiotics containing the same as an active ingredient | |
KR20040037686A (en) | Novel methylidene piperidinyl oxazolidinone derivatives and preparation method thereof | |
EP2072513A1 (en) | A cyano piperidinyl-phenil-oxazolidinone and use thereof | |
KR101264903B1 (en) | Oxazolidinone derivatives containing 2-pyrrolidone group or pharmaceutically acceptable salts thereof, and preparation method thereof | |
WO2007004032A1 (en) | Oxazolidiones containing cyclobutane as antibacterial agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO PAY ISSUE FEE |